Comment
8 Cochrane Pain, Palliative & Supportive Care Review Group. Authoring or
assessing a Cochrane Protocol, Review, or Review Update for the PaPaS
Review Group. September, 2011. http://papas.cochrane.org/sites/papas.
cochrane.org/files/public/uploads/PaPaSAuthorandRefereeGuidance.pdf
(accessed Aug 19, 2022).
Traumatic brain injury advances since 2017: what has
changed?
In 2017 The Lancet Neurology published its first
Commission on traumatic brain injury (TBI).1 The
Commission emphasised the massive scale of a
largely unrecognised public health challenge causing
substantial mortality and protracted morbidity across
all age groups and in all countries. The authors called
for a concerted approach to understand the origins
and mechanisms of TBI, with a strategy to develop
patient-focussed treatments, not only to save lives
but crucially to improve the long-term prognosis for
those who survive the acute phase. The Commission
has received more than 1000 citations to date, has
informed public debate, and has led to the development
of a government policy in the UK, but looking back over
5 years later, what has been achieved to prevent TBI or
to improve the lives of the nearly 50 million people
who sustain a head injury every year? Reconvening
in 2022, the Commissioners have critically appraised
their own progress,2 highlighting huge advances in
understanding, while honestly and openly emphasising
the limitations of current knowledge, and accordingly
revising their recommendations for prevention, critical
care, and research. Common themes emerge from their
2022 report, which can be summarised under the four
Ps: prevention, personalised stratification, precision
treatments, and prognosis.
On prevention: since 2017, large-scale international
observational studies have described the epidemiology
of TBI in unprecedented detail. These studies include
the European-funded CENTER-TBI and the USA-funded
TRACK-TBI. These new data emphasise the importance
of road traffic incidents in low-income and middle-
income countries (LMICs) and falls in individuals
older than 65 years in high-income countries (HICs),
defining comorbidities, frailty, and alcohol misuse as
key risk factors.3,4 Developing and validating effective
behavioural and social interventions to address these
risks will be very challenging, but obtaining this
www.thelancet.com/neurology Vol 21 November 2022
9 Smith SM, Fava M, Jensen MP, et al. John D. Loeser Award lecture: size does
matter, but it isn’t everything: the challenge of modest treatment effects in
chronic pain clinical trials. Pain 2020; 161 (suppl 1): S3–13.
10 Liu KS, Snavely DB, Ball WA, Lines CR, Reines SA, Potter WZ. Is bigger better
for depression trials? J Psychiatr Res 2008; 42: 622–30.
knowledge is essential in parallel to any exploration of Published Online
September 29, 2022
underlying biological mechanisms. https://doi.org/10.1016/
On personalised stratification: although withstanding S1474-4422(22)00337-4
the tests of time, the Glasgow Coma Scale and brain See The Lancet Commissions
page 1004
CT imaging remain insensitive for most patients who
present at the mild end of the spectrum of disease
severity.5 There is therefore desperate need to develop
new prediction tools that can be used to stratify patients
for personalised clinical care. Advanced MRI techniques
remain enormously valuable but are unlikely to be
available world wide. However, recent advances in serum
and CSF biomarkers build confidence that easy-to-use
and cheap biochemical tests will become mainstream
once their clinical use is validated.6,7 For more on the all-party
parliamentary group for
On precision treatments: TBI has a complex patho­ acquired brain injury see
physiology with no two patients having an identical https://ukabif.org.uk/page/
CampaignAPPG
presentation. This heterogeneity has been a major
confounder in interventional studies. Personalised
stratification using recently discovered biomarkers
provides a new approach to accelerate treatment
discovery through targeted experimental medicine
studies or smaller trials in specific patient groups.
There is also the possibility of revisiting the most
promising treatments that unexpectedly failed to
show a treatment effect in mega-trials, but focussing
on the groups most likely to show benefit based on
a mechanism-linked biomarker. Paradoxically, there
have been few trials carried out with old people who
are at the highest risk in HICs, or with the young who
have much to gain from effective stratification and For more on CENTER-TBI see
https://www.center-tbi.eu
treatment, as younger people have longer to live with
For more on TRACK-TBI see
the consequences of the TBI. https://tracktbi.ucsf.edu/
On prognosis: based on current crude measures
of severity, most head injuries are classified as mild
and are not followed up after hospital discharge. We
therefore have limited insight into the long-term
behavioural and cognitive consequences of TBI, and
even less so for the large proportion of patients who
953
 Comment
never reach medical attention. It is essential for us
to understand the risk factors contributing to long-
term adverse sequelae if we are to develop effective
strategies for prevention that have a real effect on
the societal consequences of TBI.8,9 To obtain this
knowledge, we will need studies with very long follow-
up, which might be seen as an unappealing luxury for
cash-strapped health-care systems.
There are strong synergies between each of the
four Ps: advancing one will benefit the others. There
are also common themes, perhaps the most important
ones being data sharing and the need to integrate the
same standardised research measures into routine
clinical practice. Although the sharing of clinical data
presents ethical and legal challenges, particularly on an
international level, failing to capitalise on its potential
will delay progress, resulting in more deaths and more
disability, and maintaining the huge economic cost
of TBI at around US$400 billion annually. There is an
urgent need to address this challenge now, working
closely with patients and families to maintain trust and
confidence.
Bringing together 103 authors from 19 countries,
the 2022 Commission had a serious job on its hands:
how was it possible to reach a consensus and to distil
inevitably diverse views into concise and deliverable
recommendations? Much credit goes to the leadership
provided by Andrew Maas, David Menon, and
Geoffrey Manley, who have brought the community
together through the single high-level ambition
to minimise the impact of TBI globally. Their next
challenge is how to deliver on the 48 recommendations
that provide a blueprint for progress. Dividing up the
tasks will be necessary, and overall co-ordination will
be essential, particularly because the greatest impact
954
will probably come through behavioural change at
the population level. This work will require local and
international political backing and cultural change over
a sustained period of time. Strong support from WHO,
and growing interest from national governments10 will
be essential to ensure that research funding is sustained
at a sufficient level across the globe—and for long
enough—to have the desired effect.
I report no competing interests.
Patrick F Chinnery
pfc25@cam.ac.uk
Department of Clinical Neuroscience, and the Medical Research Council
Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0QQ, UK
1 Maas AIR, Menon DK, Adelson PD, et al. Traumatic brain injury: integrated
approaches to improve prevention, clinical care, and research. Lancet Neurol
2017; 16: 987–1048.
2 Maas AIR, Menon DK, Manley GT, et al. Traumatic brain injury: progress and
challenges in prevention, clinical care, and research. Lancet Neurol 2022;
published online Sept 29. https://doi.org/10.1016/S1474-4422(22)00309-X.
3 Lecky FE, Otesile O, Marincowitz C, et al. The burden of traumatic brain
injury from low-energy falls among patients from 18 countries in the
CENTER-TBI Registry: a comparative cohort study. PLoS Med 2021;
18: e1003761.
4 Steyerberg EW, Wiegers E, Sewalt C, et al. Case-mix, care pathways, and
outcomes in patients with traumatic brain injury in CENTER-TBI:
a European prospective, multicentre, longitudinal, cohort study.
Lancet Neurol 2019; 18: 923–34.
5 Smits M, Dippel DW, de Haan GG, et al. External validation of the Canadian
CT Head Rule and the New Orleans Criteria for CT scanning in patients with
minor head injury. JAMA 2005; 294: 1519–25.
6 Bazarian JJ, Biberthaler P, Welch RD, et al. Serum GFAP and UCH-L1 for
prediction of absence of intracranial injuries on head CT (ALERT-TBI):
a multicentre observational study. Lancet Neurol 2018; 17: 782–89.
7 Okonkwo DO, Puffer RC, Puccio AM, et al. Point-of-care platform blood
biomarker testing of glial fibrillary acidic protein versus S100 calcium-
binding protein b for prediction of traumatic brain injuries: a transforming
research and clinical knowledge in traumatic brain injury study.
J Neurotrauma 2020; 37: 2460–67.
8 Dijkers MP, Marwitz JH, Harrison-Felix C. Thirty years of National Institute
on Disability, Independent Living, and Rehabilitation Research traumatic
brain injury model systems center research-an update. J Head Trauma Rehabil
2018; 33: 363–74.
9 Ponsford J, Harrison-Felix C, Ketchum JM, Spitz G, Miller AC, Corrigan JD.
Outcomes 1 and 2 years after moderate to severe traumatic brain injury:
an international comparative study. Arch Phys Med Rehabil 2021;
102: 371–77.
10 Menon DK, Bryant C. Time for change in acquired brain injury. Lancet Neurol
2019; 18: 28.
www.thelancet.com/neurology Vol 21 November 2022